부산대학교 도서관

Cognitive decline in patients with Alzheimer's disease (AD) is associated with elevated brain levels of amyloid β protein (Aβ), particularly neurotoxic A[β.sub.1-42]. Angiotensin-converting enzyme (ACE) can degrade A[β.sub.1-42], and ACE overexpression in myelomonocytic cells enhances their immune function. To examine the effect of targeted ACE overexpression on AD, we crossed [ACE.sup.10/10] mice, which overexpress ACE in myelomonocytes using the c-fms promoter, with the transgenic [APP.sub.SWE]/[PS1.sub.δE9] mouse model of AD ([AD.sup.+]). Evaluation of brain tissue from these [AD.sup.+][ACE.sup.10/10] mice at 7 and 13 months revealed that levels of both soluble and insoluble brain A[β.sub.1-42] were reduced compared with those in [AD.sup.+] mice. Furthermore, both plaque burden and astrogliosis were drastically reduced. Administration of the ACE inhibitor ramipril increased Aβ levels in [AD.sup.+][ACE.sup.10/10] mice compared with the levels induced by the ACE-independent vasodilator hydralazine. Overall, [AD.sup.+][ACE.sup.10/10] mice had less brain-infiltrating cells, consistent with reduced AD-associated pathology, though ACE-overexpressing macrophages were abundant around and engulfing Aβ plaques. At 11 and 12 months of age, the [AD.sup.+][ACE.sup.10/WT] and [AD.sup.+][ACE.sup.10/10] mice were virtually equivalent to non-AD mice in cognitive ability, as assessed by maze-based behavioral tests. Our data demonstrate that an enhanced immune response, coupled with increased myelomonocytic expression of catalytically active ACE, prevents cognitive decline in a murine model of AD.
Introduction Alzheimer's disease (AD) is the most common cause of dementia in the elderly and is characterized by a progressive deterioration of cognitive and behavioral functions. Indeed, throughout the world, [...]